This project will exploit the power of zebrafish genetics to discover new genes that are essential for myelination in the vertebrate nervous system. The myelin sheath wraps axons and allows for rapid transmission of action potentials in vertebrates. Disruption of myelin causes debilitating human diseases, including Multiple Sclerosis and hereditary neuropathies. Gaps in the understanding of the regulatory networks that govern the formation of myelinated axons have hindered progress toward therapies to repair myelin damage and prevent the loss of axons in affected nerves. To investigate the genetic mechanisms that control myelination, this project uses a zebrafish genetic screen to isolate mutations in genes with essential functions in the formation of myelinated axons. Preliminary studies have identified 13 mutations that :specifically disrupt the glial cells that form myelin. Initial phenotypic characterization suggests that two classes of mutants will be especially useful in the genetic dissection of myelination. (1) Seven mutations specifically disrupt myelinating glial cells in the peripheral nervous system, and in some cases axonal defects are also apparent. These mutations may represent zebrafish models of Charcot-Marie-Tooth disease and other hereditary neuropathies. (2) Myelinating glial cells in two other mutants have abnormal morphology, suggesting the hypothesis that these genes are essential for the terminal differentiation of myelinating glia.
the specific aims of this project are (1) to isolate mutations in new genes with essential functions in myelination in an expanded genetic screen, (2) to define the functions of the mutated genes by analysis of glial development and myelin ultrastructure in the mutants, and (3) to discover the biochemical basis of the genes' function in myelination by molecular analysis of the mutations. This project will define new zebrafish models of important myelin disorders in human, discover new genes with essential functions in myelination, and provide new avenues toward therapies for myelin repair and prevention of axonal damage after demyelination. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CDF-4 (50))
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Tagle, Danilo A
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Stanford University
Anatomy/Cell Biology
Schools of Medicine
United States
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Meireles, Ana M; Shen, Kimberle; Zoupi, Lida et al. (2018) The Lysosomal Transcription Factor TFEB Represses Myelination Downstream of the Rag-Ragulator Complex. Dev Cell 47:319-330.e5
Stratman, Amber N; Pezoa, Sofia A; Farrelly, Olivia M et al. (2017) Interactions between mural cells and endothelial cells stabilize the developing zebrafish dorsal aorta. Development 144:115-127
Shen, Kimberle; Sidik, Harwin; Talbot, William S (2016) The Rag-Ragulator Complex Regulates Lysosome Function and Phagocytic Flux in Microglia. Cell Rep 14:547-559
Koudelka, Sigrid; Voas, Matthew G; Almeida, Rafael G et al. (2016) Individual Neuronal Subtypes Exhibit Diversity in CNS Myelination Mediated by Synaptic Vesicle Release. Curr Biol 26:1447-55
Ravenscroft, Gianina; Nolent, Flora; Rajagopalan, Sulekha et al. (2015) Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita. Am J Hum Genet 96:955-61
Sidik, Harwin; Talbot, William S (2015) A zinc finger protein that regulates oligodendrocyte specification, migration and myelination in zebrafish. Development 142:4119-28
Paavola, Kevin J; Sidik, Harwin; Zuchero, J Bradley et al. (2014) Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126. Sci Signal 7:ra76
Campbell, Philip D; Shen, Kimberle; Sapio, Matthew R et al. (2014) Unique function of Kinesin Kif5A in localization of mitochondria in axons. J Neurosci 34:14717-32
Zaucker, Andreas; Mercurio, Sara; Sternheim, Nitzan et al. (2013) notch3 is essential for oligodendrocyte development and vascular integrity in zebrafish. Dis Model Mech 6:1246-59
Glenn, Thomas D; Talbot, William S (2013) Signals regulating myelination in peripheral nerves and the Schwann cell response to injury. Curr Opin Neurobiol 23:1041-8

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